Mechanisms and Epidemiology of Drug Hypersensitivity: From Neutrophil Activation to <scp>ER</scp> Stress and Global Anaphylaxis Patterns

In this month's editorial, the Editors of the journal have selected three articles that represent major advances in drug allergy diagnostics, mucosal immunology, and global allergy epidemiology. The first article, “Assessment of Patients With Beta-Lactams Positive Provocation Tests by Biomarkers of IgG-Related Neutrophil Activation” [], addresses the diagnostic challenges in beta-lactam allergy—a label that affects up to 10% of the population and leads to unnecessary avoidance, increased health care costs, and antimicrobial resistance [2-4]. Traditional diagnostic tools, such as skin tests and sIgE assays, have demonstrated limited sensitivity (30.7% and 19.3% respectively) despite high specificity, as shown in a recent meta-analysis of over 31,000 patients [5]. This article investigates novel biomarkers including neutrophil activation and NET formation in confirmed beta-lactam allergic individuals, comparing patients with immediate hypersensitivity to drug-provocation-test controls. Authors found that drug-specific IgG, rather than IgE, correlated with elevated neutrophil extracellular trap formation, DNAse activity, and neutrophil elastase—suggesting that non-IgE immune pathways may play a substantial role in certain allergic phenotypes. Their data not only highlight diagnostic gaps with conventional approaches but also pave the way for the development of neutrophil marker panels to improve risk stratification and guide de-labeling interventions. Future investigations should focus on validating these biomarkers in diverse populations and evaluating their predictive value for severe reactions, thereby reshaping both laboratory and clinical protocols. Figure 1 below shows the graphical abstract representing the summary of this paper. The second article, “Excessive Endoplasmic Reticulum Stress in B Cells Associates with the Local Immunoglobulin Production in Severe Type 2 Chronic Rhinosinusitis with Nasal Polyps” [6], provides an in-depth analysis of how subcellular stress contributes to local immune dystegulation in chronic rhinosinusitis with nasal polyps (CRSwNP). CRSwNP is a form of upper airway disease characterised by persistent, type 2 inflammation and marked tissue eosinophilia, often escaping conventional therapies and resulting in significant morbidity [4]. Increasing evidence has revealed that local antibody production, particularly of IgE, is a significant driver of disease activity and resistance to treatment [7]. However, the cellular processes by which local immune cells, especially B cells, produce excessive immunoglobulins remain largely unclear. In this study, elevated endoplasmic reticulum (ER) stress signatures were observed in the nasal polyps of CRSwNP patients, most notably with increased expression of HSPA5 and HSP90B1—two ER chaperone proteins strongly correlated with local IGHE and type 2 inflammatory gene expression compared to control nasal tissue. Electron microscopy revealed dilated ER and lumen enlargement in B cells from nasal polyps, while immunofluorescence and co-localisation studies encompassed markers like MZB1 and demonstrated that ER stress signatures in CRSwNP predominantly originate from B and plasma cells. Functional in vitro assays further showed that MZB1 stimualtion promoted the expression of ER stress markers and IgE, implicating a key feedback look between ER stress and immunoglobulin production in the local microenvironment. Notably, induction of ER stress elevated IGHE expression, and anti-IgE interventions reduced ER stress marker expression in cultured cells. Collectively, these results establish that excessive B cell ER stress is a feature of severe type 2 CRSwNP, likely amplifying local IgE-mediated inflammation. Moving forward, targeting ER stress pathways in B cells may provide new opportunities for therapeutic intervention, and future research will be critical to assess the translational potential of modulating ER stress for disease control and symptom resolution. Figure 2 represents the graphical abstract illustrating the key findings of this paper. The third article, “Global Burden of Drug-Induced Anaphylaxis Associated With 33 Classes of Antibiotics (1968–2024): A Pharmacovigilance Analysis” [8], provides a panoramic evaluation of antibiotic-induced anaphylaxis by analysing over 144,000 global pharmacovigilance reports spanning more than half a century. Drug-induced anaphylaxis, while relatively rare, remains among the most serious adverse events in clinical medicine—with antibiotics as the most frequent implicated agents [9]. The authors systematically evaluated spontaneous reports, focusing on signal detection metric such as reporting odds ratios (ROR) and information component (IC) statistics, to assess risk profiles across age, sex, and antibiotic classes. Three groups—penicillins (27.4% of cases), other beta-lactam antibiotics (43.9%), and quinolones (14.0%)—were identified as accounting for the highest burden of cases, with strong signal strength for each (e.g., bete-lactams ROR 27.59 and IC 4.48). Clinically, onset was typically rapid, with a median time-to-onset of 1 day, reflecting the acute and unpredictable nature of anaphylaxis. While most cases resulted in recovery (over 96%), a fatality rate of 1.23% underscores the continued threat to patient safety and the need for enhanced vigilance. The authors conclude that, despite the inability to assert causality, their analysis highlights significant gaps in standardised diagnosis, patient risk stratification, and long-term management of drug-induced anaphylaxis. The article calls for the development of universal grading criteria for anaphylaxis, further exploration of patient-specific risk factors—including genomics and comorbidity profiles—and better tracking of outcomes to inform prevention and care strategies. Figure 3 provides a graphical abstract summarising the key findings from this paper. The authors declare no conflicts of interest.